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EP2334645B1 - Process for the synthesis of fluorinated cyclic compounds - Google Patents

Process for the synthesis of fluorinated cyclic compounds Download PDF

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Publication number
EP2334645B1
EP2334645B1 EP09783436.0A EP09783436A EP2334645B1 EP 2334645 B1 EP2334645 B1 EP 2334645B1 EP 09783436 A EP09783436 A EP 09783436A EP 2334645 B1 EP2334645 B1 EP 2334645B1
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process according
formula
compound
reaction
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EP2334645A1 (en
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Max Braun
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Solvay SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for the synthesis of fluorinated cyclic compounds.
  • Fluorinated cyclic compounds are useful for example as intermediates for the preparation of various herbicides, insecticides, miticides, pesticides etc.
  • U.S. patent application US 2006/0128702 A1 describes the synthesis of 3-trifluoromethyl-1H-Pyrazole (TFPZO) by reacting 4-ethoxy-1,1,1-trifluoro-3-buten-2-one with hydrazine dihydrochloride.
  • Atherton and Fields, J. Chem. Soc. (C), 1968, p.1507-1513 describe the synthesis of 3-trifluoromethyl-1H-Pyrazole from 2,2,2-trifluorodiazoethane.
  • the TFPZO compound is used as intermediate in chemical synthesis.
  • European patent application EP-A-163280 discloses the manufacture of 2-hydroxy-4-trifluoromethyl pyrimidine (TFPMO) from the reaction product of TFAH with EVE.
  • TFPMO 2-hydroxy-4-trifluoromethyl pyrimidine
  • the TFPMO compound is used as intermediate in chemical synthesis, to produce pyrimidinylphosphates as pesticides.
  • the invention concerns in consequence a process for the manufacture of a cvclic compound of formula (I) :
  • the addition product of an acid chloride with a vinyl ether as specified above is particularly suitable as starting material for producing cyclic compounds as detailed above. Overall yield starting from acid chloride and vinyl ether is good. A purification of the addition product is unnecessary before further reaction.
  • the addition product in particular if hydrogen chloride is present, may increase the reaction rate in the reaction with the compound selected from hydrazine or its hydrate or hydrochloride, urea, thiourea, methyl ester of malonic acid monoamide, ethyl ester of malonic acid monoamide, methyl ester of 2-cyano-acetic acid and ethyl ester of 2-cyano-acetic acid and allow for easier separation of the cyclic compound produced from the reaction mixture.
  • R1 is selected from CF 3 , CF 2 H and CF 2 Cl.
  • a CF 3 group is more particularly preferred.
  • R1 preferably is CF 2 Cl.
  • Acid chlorides used in the present invention can be obtained, for example, by photoxidation of halogenated precursor alkanes, in particular as described in US 5,569,782 .
  • trifluoroacetyl chloride which is a particularly preferred starting material in the present invention, can be obtained by photooxidation of 1,1,1-Trifluoro-2,2-dichloroethane (HCFC-123).
  • R 2 is selected from a C1 to C4 alkyl group, preferably a methyl, an ethyl, an isopropyl or a n-butyl group and is more preferably an ethyl group.
  • the acid chloride is trifluoroacetyl chloride and the vinyl ether is ethyl vinyl ether or methyl vinyl ether, more preferably ethyl vinyl ether.
  • Reactants for the addition product of step (a) in step (b) are hydrazine or its hydrate or hydrochloride, urea, thiourea, methyl ester of malonic acid monoamide, ethyl ester of malonic acid monoamide, methyl ester of 2-cyano-acetic acid and ethyl ester of 2-cyano-acetic acid.
  • step (b) the reaction of step (b) is generally carried out at a temperature in the range from -15° C to +80°C, preferably from 0° C to +20°C.
  • the reaction of step (b) can be carried out in the presence of a non-hindered amine.
  • Non-hindered amines refers to chemical compounds containing an amine functional group bonded to non-sterically hindering groups.
  • Typical examples of non-sterically hindering groups are short linear aliphatic groups such as methyl, ethyl, propyl and n-butyl
  • Typical examples of non-hindered amines are for example methylamine, diethylamine, triethylamine and tri-n-butylamine.
  • Triethylamine is most preferred non-hindered amine.
  • the molar ratio of the non-hindered amine to the compound selected from hydrazine or its hydrate or hydrochloride, urea, thiourea, methyl ester of malonic acid monoamide, ethyl ester of malonic acid monoamide, methyl ester of 2-cyano-acetic acid and ethyl ester of 2-cyano-acetic acid is advantageously from 0.5:1 to 1.7:1, preferably from 0.6:1 to 1.5:1, and more preferably from 0.8:1 to 1.2:1. Most preferably, the molar ratio is about 1.
  • the reaction of step (b) can optionally be carried out in the presence of an additive.
  • additive generally increases the polarity of the reaction medium.
  • Ionic liquids can be suitably used as additives.
  • Typical examples of additives are for instance 1,3-dialkylimidazolium or 1,3-dialkyl piridinium salts in particular 1-ethyl-3-methylimidazolium trifluoromethanesulfonate (EMIMOtf).
  • Amines such as 4-Dimethylaminopyridine (DMAP), Diazabicyclo [5.4.0] undec-7-ene (DBU) and Diazabicyclononan (DBN) as such or under salt form, for example as trifluoroacetic acid salt can also be suitably used as additive.
  • DMAP 4-Dimethylaminopyridine
  • DBU Diazabicyclo [5.4.0] undec-7-ene
  • DBN Diazabicyclononan
  • trifluoroacetic acid salt can also be suitably used as additive.
  • the term "ionic liquid” refers to a homogeneous composition consisting of a single salt (one cationic species and one anionic species) or it may refer to a heterogeneous composition containing more than one species of cation and/or more than one species of anion.
  • step (b) the reaction of step (b) is often carried out in an organic solvent, in particular a polar organic solvent.
  • Alcohols such as methanol or ethanol give good results in the reaction of step (b).
  • Methanol is particularly preferred.
  • the process according to the invention suitably further comprises isolating the compound of formula (I) from the reaction medium of step (b) by solid/liquid separation, for example filtration or by distillation.
  • the addition product comprises a compound of formula (IV) : wherein X, R 1 and R 2 are as defined above.
  • the addition product comprises a compound of formula (V) : wherein R 2 is as defined above.
  • Compounds of formulae (IV) and (V) can be advantageously used as starting materials to form cyclic compounds, in particular in accordance with the process according to the invention.
  • a compound of formula (IV) or (V) can thus be used as reagent in an addition reaction to form a cyclic compound.
  • the addition product comprises a compound of formula (IV) or (V)
  • its content is generally at least 0.1 wt. % relative to the total weight of addition product. Often this content is at least 0.5 %. In some embodiments this content does not exceed 10 wt. %.
  • the addition product can also consist essentially of compound of formula (IV) or (V). In this case its content is generally from 90-99.9, often from 95 to 99.0 wt. % relative to the total weight of addition product.
  • the addition product comprises a compound of formula (VI) : wherein R 1 and R 2 are as defined above.
  • the addition product comprises a compound of formula (VII) : wherein R 2 is as defined above.
  • the compounds of formulae (VI) and (VII) can be obtained preferably by a process comprising (a) adding, as described above, acid chloride to vinyl ether to obtain a reaction product comprising compound of formula (IV) or (V) and (b) eliminating hydrogen chloride to produce a compound of formula (VI) or (VII) respectively.
  • Such reaction can be carried out in the presence of base such as described in US patent 5,708,174 or, preferably, in the absence of base such as described in US patent 7,405,328 .
  • the addition product comprises a compound of formula (VI) or (VII)
  • its content is generally at least 0.1 wt. % relative to the total weight of addition product. Often this content is at least 0.5 %. In some embodiments this content does not exceed 10 wt. %.
  • the addition product can also consist essentially of compound of formula (VI) or (VII). In this case its content is generally from 90-99.9, often from 95 to 99.0 wt. % relative to the total weight of addition product.
  • the addition product can be a mixture of compounds of formula (IV) and (VI) or (V) and (VII) respectively.
  • the molar ratio between compounds (IV) and (V) on the one hand and (VI) and (VII) on the other hand is generally from 0.01 to 100, preferably from 0.1 to 10.
  • the crude product from the addition reaction (a) may notably, in addition to the addition product as described here before, contain hydrogen chloride.
  • HCl is fed to step (b).
  • HCl, produced in step (a) may suitably be fed to step (b).
  • step (b) it has been found that it is possible to precipitate the heterocycle from the reaction medium of step (b) by addition of HCl and to isolate it for example by filtration.
  • the HCl addition can be carried out, for example during reaction or during work-up.
  • the invention also concerns a process for the synthesis of a cyclic compound of formula (I) :
  • CETFBO 4.0 moles of trifluoroacetyl chloride was condensed in a 3-necked flask which was cooled at around -30°C during ca. 2 hours. 4.0 moles of ethyl vinyl ether was added dropwise to the liquid trifluoroacetyl chloride cooled at around -30°C during about 2.5 hours. CETFBO could be obtained quantitatively without any elimination of HCl.
  • MMA methylmalonamide
  • ETFBO which had been manufactured by addition of TFAC to ethyl vinyl ether, was then added dropwise under ice cooling and over a period of about 30 min whereby the temperature of the reaction mixture was kept under 10°C.
  • the reaction mixture was then further stirred at room temperature for 20 h.
  • a concentrated HCl solution (2N) was added to the solution until a pH of 3 was obtained.
  • the organic phase was washed with water and dried over sodium sulfate. After removing the volatile compounds on a rotary evaporator, the crude product could be obtained in 86 % yield.
  • MTFPMOC was obtained with a purity > 98% (GC).

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Description

  • The present invention relates to a process for the synthesis of fluorinated cyclic compounds.
  • Fluorinated cyclic compounds are useful for example as intermediates for the preparation of various herbicides, insecticides, miticides, pesticides etc. U.S. patent application US 2006/0128702 A1 describes the synthesis of 3-trifluoromethyl-1H-Pyrazole (TFPZO) by reacting 4-ethoxy-1,1,1-trifluoro-3-buten-2-one with hydrazine dihydrochloride. Atherton and Fields, J. Chem. Soc. (C), 1968, p.1507-1513 describe the synthesis of 3-trifluoromethyl-1H-Pyrazole from 2,2,2-trifluorodiazoethane. The TFPZO compound is used as intermediate in chemical synthesis. European patent application EP-A-163280 discloses the manufacture of 2-hydroxy-4-trifluoromethyl pyrimidine (TFPMO) from the reaction product of TFAH with EVE. The TFPMO compound is used as intermediate in chemical synthesis, to produce pyrimidinylphosphates as pesticides.
  • It is an object of the present invention to provide an efficient process for manufacturing fluorinated nitrogen containing heterocycles which allows for good yields and product purities, starting from readily available starting materials.
  • The invention concerns in consequence a process for the manufacture of a cvclic compound of formula (I) :
    Figure imgb0001
    • wherein R1 is selected from CF3, CF2H and CF2Cl
    • Z-A-Y is selected from N-NH, N-C(=O)-NH, N-C(=S)-NH, N-C(=O)-CH(COOMe) and N-C(=O)-CH(COOEt)
    • which comprises (a) adding an acid halide of formula R1-C(O)-X wherein X is chlorine and R1 has the meaning given above, to a vinyl ether of formula

              CH2=CH-OR2     (II)

      wherein R2 is a C1 to C4 alkyl group to produce an addition product,
    • and (b) said addition product is reacted with a selected from hydrazine or its hydrate or hydrochloride, urea, thiourea, methyl ester of malonic acid monoamide, ethyl ester of malonic acid monoamide, methyl ester of 2-cyano-acetic acid and ethyl ester of 2-cyano-acetic acid, and wherein the addition product supplied to step (b) is a crude product from step (a).
  • It has been found, surprisingly, that the addition product of an acid chloride with a vinyl ether as specified above is particularly suitable as starting material for producing cyclic compounds as detailed above. Overall yield starting from acid chloride and vinyl ether is good. A purification of the addition product is unnecessary before further reaction. The addition product, in particular if hydrogen chloride is present, may increase the reaction rate in the reaction with the compound selected from hydrazine or its hydrate or hydrochloride, urea, thiourea, methyl ester of malonic acid monoamide, ethyl ester of malonic acid monoamide, methyl ester of 2-cyano-acetic acid and ethyl ester of 2-cyano-acetic acid and allow for easier separation of the cyclic compound produced from the reaction mixture.
  • In the process according to the invention, R1 is selected from CF3, CF2H and CF2Cl. A CF3 group is more particularly preferred.
  • In another aspect, R1 preferably is CF2Cl.
  • In the process according to the invention, X is Cl.
  • Acid chlorides used in the present invention can be obtained, for example, by photoxidation of halogenated precursor alkanes, in particular as described in US 5,569,782 . In particular, trifluoroacetyl chloride, which is a particularly preferred starting material in the present invention, can be obtained by photooxidation of 1,1,1-Trifluoro-2,2-dichloroethane (HCFC-123).
  • In the process according to the invention, R2 is selected from a C1 to C4 alkyl group, preferably a methyl, an ethyl, an isopropyl or a n-butyl group and is more preferably an ethyl group.
  • Consequently, in a most preferred aspect, the acid chloride is trifluoroacetyl chloride and the vinyl ether is ethyl vinyl ether or methyl vinyl ether, more preferably ethyl vinyl ether.
  • In the process according to the invention Z-A-Y is selected from N-NH, N-C(=O)-NH, N-C(=S)-NH, N-C(=O)-CH(COOMe) and N-C(=O)-CH(COOEt). Reactants for the addition product of step (a) in step (b) are hydrazine or its hydrate or hydrochloride, urea, thiourea, methyl ester of malonic acid monoamide, ethyl ester of malonic acid monoamide, methyl ester of 2-cyano-acetic acid and ethyl ester of 2-cyano-acetic acid.
  • In the process according to the invention, the reaction of step (b) is generally carried out at a temperature in the range from -15° C to +80°C, preferably from 0° C to +20°C.
  • In the process according to the invention, the reaction of step (b) can be carried out in the presence of a non-hindered amine. Non-hindered amines refers to chemical compounds containing an amine functional group bonded to non-sterically hindering groups. Typical examples of non-sterically hindering groups are short linear aliphatic groups such as methyl, ethyl, propyl and n-butyl Typical examples of non-hindered amines are for example methylamine, diethylamine, triethylamine and tri-n-butylamine.
  • Triethylamine is most preferred non-hindered amine.
  • In the process according to the invention, the molar ratio of the non-hindered amine to the compound selected from hydrazine or its hydrate or hydrochloride, urea, thiourea, methyl ester of malonic acid monoamide, ethyl ester of malonic acid monoamide, methyl ester of 2-cyano-acetic acid and ethyl ester of 2-cyano-acetic acid is advantageously from 0.5:1 to 1.7:1, preferably from 0.6:1 to 1.5:1, and more preferably from 0.8:1 to 1.2:1. Most preferably, the molar ratio is about 1.
  • In the process according to the invention, the reaction of step (b) can optionally be carried out in the presence of an additive. Such additive generally increases the polarity of the reaction medium. Ionic liquids can be suitably used as additives. Typical examples of additives are for instance 1,3-dialkylimidazolium or 1,3-dialkyl piridinium salts in particular 1-ethyl-3-methylimidazolium trifluoromethanesulfonate (EMIMOtf). Amines such as 4-Dimethylaminopyridine (DMAP), Diazabicyclo [5.4.0] undec-7-ene (DBU) and Diazabicyclononan (DBN) as such or under salt form, for example as trifluoroacetic acid salt can also be suitably used as additive.
  • For the purpose of the present invention, the term "ionic liquid" refers to a homogeneous composition consisting of a single salt (one cationic species and one anionic species) or it may refer to a heterogeneous composition containing more than one species of cation and/or more than one species of anion.
  • In the process according to the invention, the reaction of step (b) is often carried out in an organic solvent, in particular a polar organic solvent. Alcohols such as methanol or ethanol give good results in the reaction of step (b).
  • Methanol is particularly preferred.
  • The process according to the invention suitably further comprises isolating the compound of formula (I) from the reaction medium of step (b) by solid/liquid separation, for example filtration or by distillation.
  • In a first embodiment of the process according to the invention the addition product comprises a compound of formula (IV) :
    Figure imgb0002
     wherein X, R1 and R2 are as defined above.
  • In a preferred aspect of this first embodiment the addition product comprises a compound of formula (V) :
    Figure imgb0003
     wherein R2 is as defined above.
  • Compounds of formulae (IV) and (V) can be advantageously used as starting materials to form cyclic compounds, in particular in accordance with the process according to the invention. A compound of formula (IV) or (V) can thus be used as reagent in an addition reaction to form a cyclic compound.
  • When the addition product comprises a compound of formula (IV) or (V), its content is generally at least 0.1 wt. % relative to the total weight of addition product. Often this content is at least 0.5 %. In some embodiments this content does not exceed 10 wt. %.
  • The addition product can also consist essentially of compound of formula (IV) or (V). In this case its content is generally from 90-99.9, often from 95 to 99.0 wt. % relative to the total weight of addition product.
  • In a second embodiment of the process according to the invention, the addition product comprises a compound of formula (VI) :
    Figure imgb0004
     wherein R1 and R2 are as defined above.
  • In a preferred aspect of the second embodiment, the addition product comprises a compound of formula (VII) :
    Figure imgb0005
     wherein R2 is as defined above.
  • The compounds of formulae (VI) and (VII) can be obtained preferably by a process comprising (a) adding, as described above, acid chloride to vinyl ether to obtain a reaction product comprising compound of formula (IV) or (V) and (b) eliminating hydrogen chloride to produce a compound of formula (VI) or (VII) respectively. Such reaction can be carried out in the presence of base such as described in US patent 5,708,174 or, preferably, in the absence of base such as described in US patent 7,405,328 .
  • When the addition product comprises a compound of formula (VI) or (VII), its content is generally at least 0.1 wt. % relative to the total weight of addition product. Often this content is at least 0.5 %. In some embodiments this content does not exceed 10 wt. %.
  • The addition product can also consist essentially of compound of formula (VI) or (VII). In this case its content is generally from 90-99.9, often from 95 to 99.0 wt. % relative to the total weight of addition product.
  • In the process according to the invention, the addition product can be a mixture of compounds of formula (IV) and (VI) or (V) and (VII) respectively. In this case the molar ratio between compounds (IV) and (V) on the one hand and (VI) and (VII) on the other hand is generally from 0.01 to 100, preferably from 0.1 to 10.
  • In particular, when the addition reaction in the process according to the invention is carried out in the absence of base, the crude product from the addition reaction (a) may notably, in addition to the addition product as described here before, contain hydrogen chloride.
  • In one particular embodiment of the process according to the invention, HCl is fed to step (b). In particular such HCl, produced in step (a) may suitably be fed to step (b).
  • In particular in this embodiment, it has been found that it is possible to precipitate the heterocycle from the reaction medium of step (b) by addition of HCl and to isolate it for example by filtration. The HCl addition can be carried out, for example during reaction or during work-up.
  • The invention also concerns a process for the synthesis of a cyclic compound of formula (I) :
    Figure imgb0006
    • wherein R1 is selected from CF3, CF2H and CF2Cl
    • Z-A-Y is selected from N-NH, N-C(=O)-NH, N-C(=S)-NH, N-C(=O)-CH(COOMe) and N-C(=O)-CH(COOEt)
    • wherein an addition product obtainable by addition of an acid chloride of formula R1-C(O)-X wherein X is chlorine and R1 has the meaning given above, to a vinyl ether of formula

              CH2=CH-OR2     (II)

      wherein R2 is a C1 to C4 alkyl group is reacted with a compound selected from hydrazine or its hydrate or hydrochloride, urea, thiourea, methyl ester of malonic acid monoamide, ethyl ester of malonic acid monoamide, methyl ester of 2-cyano-acetic acid and ethyl ester of 2-cyano-acetic acid in the presence of hydrogen chloride.
  • The definitions and preferences described above in the framework of the manufacturing process according to the invention equally apply to the synthesis process.
  • The following examples are intended to illustrate the invention in further detail without limiting its scope.
    • Example 1 Manufacture of 6-(trifluoromethyl)pyrimidin-2(1H)-on
  • To a solution of 8.74 moles of urea in 2.2L of methanol in a 3-necked flask, equipped with a mechanical stirrer, a reflux condenser and a dropping funnel was added dropwise over about 3 hours under N2 atmosphere an equimolar amount of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (ETFBO) which had been manufactured by addition of trifluoroacetyl chloride to ethyl vinyl ether. The temperature of the reaction mixture was kept below 15°C. After 15 min, 1.35 L of a concentrated HCl solution (32 %) was added to the cooled suspension obtained and a clear solution was obtained. The solution was slowly heated to 60°C and after 2 hours stirring, a suspension was formed. After overnight stirring at 60°C and subsequently 1 h stirring at 0 to 5°C, the precipitate was filtered off. The residue was washed with water until neutral pH and subsequently with hexane (ca. 500ml). After overnight drying on a rotary evaporator under reduced pressure in a 2L flask, 6-(trifluoromethyl)pyrimidin-2(1H)-on was obtained as colorless cristals. The yield was 1.2 kg, (85 % of the theoretical yield).
    • Example 2 Manufacture of 3-(trifluoromethyl)1H-pyrazole
  • To a solution of 4.4 moles hydrazine.hydrochloride in 2.2L of methanol in a 3-necked flask, equipped with a mechanical stirrer, a reflux condenser and a dropping funnel an equimolar amount of ETFBO which had been manufactured by addition of trifluoroacetyl chloride to ethyl vinyl ether was added dropwise over about 4 hours under N2 atmosphere. The temperature of the reaction mixture was kept below 15°C. After 12h of reflux, the reaction batch was filtered in a 2L flask and concentrated under vacuum (An identical batch was made under the same conditions, yield of both crude products was ca. 95 %). Subsequently, the combined crude product was purified by shortpass-vacuum distillation at 27 mbar. The yield was 1105 g, which corresponded to 92 % of the theoretical yield.
    • Example 3 Manufacture of 6-(trifluoromethyl)pyrimidin-2(1H)-on from CETFBO
  • Synthesis of CETFBO : 4.0 moles of trifluoroacetyl chloride was condensed in a 3-necked flask which was cooled at around -30°C during ca. 2 hours. 4.0 moles of ethyl vinyl ether was added dropwise to the liquid trifluoroacetyl chloride cooled at around -30°C during about 2.5 hours. CETFBO could be obtained quantitatively without any elimination of HCl.
  • Synthesis of 6-(trifluoromethyl)pyrimidin-2(1H)-on: 0.12 moles of the cooled solution of CETFBO was added dropwise to a stirred solution of 0.1 moles of urea in 25 mL of methanol in a 3-necked flask whereby the temperature was kept below 5°C. The solution was stirred overnight at room temperature. The brown colored solution obtained was then heated at 70°C for 4,5 hours. Upon cooling the solution in an ice-bath, 6-(trifluoromethyl)pyrimidin-2(1H)-on was obtained as pale beige crystals which were filtered off and washed with water. After drying on a rotary evaporator under reduced pressure, 6-(trifluoromethyl)pyrimidin-2(1H)-on was obtained in 82 % yield.
    • Example 4 Manufacture of 3-pyridinecarboxylic acid, 1,2-dihydro-2-oxo-6-(trifluoromethyl)-methyl ester (MTFPMOC)
  • 420 mmoles of methylmalonamide (MMA) was added to ice cooled triethylamine (420 mmoles) over a period of about 20 min under vigerous stirring. ETFBO which had been manufactured by addition of TFAC to ethyl vinyl ether,was then added dropwise under ice cooling and over a period of about 30 min whereby the temperature of the reaction mixture was kept under 10°C. The reaction mixture was then further stirred at room temperature for 20 h. A concentrated HCl solution (2N) was added to the solution until a pH of 3 was obtained. After extraction of the solution with ethyl acetate, the organic phase was washed with water and dried over sodium sulfate. After removing the volatile compounds on a rotary evaporator, the crude product could be obtained in 86 % yield. After crystallisation from methanol/water, MTFPMOC was obtained with a purity > 98% (GC).
    • Example 5 Manufacture of 3-Pyridinecarboxylic acid, 1,2-dihydro-2-oxo-6-(trifluoromethyl)- ethyl ester (ETFPMOC)
  • 420 mmoles of ethylmalonamide (EMA) was added to ice cooled triethylamine (420 mmoles) over a period of about 20 min under vigerous stirring. ETFBO which had been manufactured by addition of TFAC to ethyl vinyl ether, was then added dropwise under ice cooling and over a period of about 30 min whereby the temperature of the reaction mixture was kept under 10°C. The reaction mixture was then further stirred at room temperature for 20 h. A concentrated HCl solution (2N) was added to the solution until a pH of 3 was obtained. After extraction of the solution with ethylacetate, the organic phase was washed with water and dried over sodium sulfate. After removing the volatile compounds on a rotary evaporator, the crude product could be obtained in 86 % yield. After crystallisation from methanol/water, ETFPMOC was obtained with a purity > 98% (GC).

Claims (11)

  1. A process for the manufacture of a cyclic compound of formula (I) :
    Figure imgb0007
    wherein R1 is selected from CF3, CF2H and CF2Cl
    Z-A-Y is selected from N-NH, N-C(=O)-NH, N-C(=S)-NH, N-C(=O)-CH(COOMe) and N-C(=O)-CH(COOEt)
    which comprises (a) adding an acid halide of formula R1-C(O)-X wherein X is chlorine and R1 has the meaning given above, to a vinyl ether of formula

            CH2=CH-OR2     (II)

    wherein R2 is a C1 to C4 alkyl group to produce an addition product,
    and (b) said addition product is reacted with a compound selected from hydrazine or its hydrate or hydrochloride, urea, thiourea, methyl ester of malonic acid monoamide, ethyl ester of malonic acid monoamide, methyl ester of 2-cyano-acetic acid and ethyl ester of 2-cyano-acetic acid, and wherein the addition product supplied to step (b) is a crude product from step (a).
  2. The process according to claim 1, wherein the addition product comprises a compound of formula (IV) :
    Figure imgb0008
    wherein R1 is selected from CF3, CF2H and CF2Cl
    X is Cl and
    R2 is a C1 to C4 alkyl group,
    preferably wherein R1 is CF3, corresponding to a compound of formula (V)
    Figure imgb0009
     wherein R2 is a C1 to C4 alkyl group.
  3. The process according to claim 1, wherein the addition product comprises a compound of formula (VI) :
    Figure imgb0010
    wherein R1 is selected from CF3, CF2H and CF2Cl
    R2 is a C1 to C4 alkyl group, preferably wherein wherein R1 is CF3, corresponding to
    a compound of formula (VII) :
    Figure imgb0011
     wherein R2 is a C1 to C4 alkyl group.
  4. The process according to anyone of claims 1 to 3, wherein R2 is an ethyl group.
  5. The process according to any one of claims 1 to 4, wherein the reaction of step(b) is carried out in the presence of a non-hindered amine, preferably in the presence of triethylamine.
  6. The process according to anyone of claims 1 to 4 wherein the addition reaction of step(a) is carried out in the absence of a base.
  7. The process according to anyone of claims 1 to 4 or 6, wherein HCl produced in step (a) is fed to step (b).
  8. The process according to claim 6, wherein the crude product from addition reaction of step (a) contains hydrogen chloride.
  9. The process according to anyone of claims 1 to 8, wherein the reaction of step (b) is carried out at a temperature in the range from -15°C to +80°C.
  10. The process according to anyone of claims 1 to 9, which further comprises isolating the compound of formula (I) from the reaction medium of step (b) by solid/liquid separation or distillation.
  11. The process according to anyone of claims 1 to 10, wherein the compound of step (b) is selected from hydrazine or its hydrate or hydrochloride, methyl ester of malonic acid monoamide, ethyl ester of malonic acid monoamide, ethyl ester of 2-cyano-acetic acid and methyl ester of 2-cyano-acetic acid.
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